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This variantScenario
BenignPathogenic
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
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About PTEN
PTEN is a tumor suppressor gene that encodes a phosphatase converting the lipid messenger PIP3 back to PIP2 at the cell membrane, thereby restraining the AKT/mTOR signaling pathway that drives cell growth, proliferation, and survival. It is one of the most frequently mutated genes across many types of human cancer, and its loss promotes unchecked cell growth, survival, and genomic instability, partly through impaired DNA repair. Germline loss-of-function variants in PTEN cause Cowden syndrome, an inherited cancer predisposition disorder associated with elevated risk of breast and thyroid cancer.
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01The reasoning
How it was classified
The recorded framework is ClinGen PTEN VCEP v3.2. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
ACMG/AMP criteria under ClinGen PTEN VCEP v3.2, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 7 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For this frameshift variant, the PTEN VCEP's missense-specific PS1, PM5, and PP2 rules do not apply; BP1 is explicitly not applicable; PM1 is not met because residue 338 is outside the VCEP-defined catalytic motifs.
PS2, PM6, PP1, and BS4 are all applicable under the PTEN Expert Panel specification, but none can be assessed because the available case evidence contains no proband, parental, family segregation, meiosis, or non-segregation observations.
The reviewed literature extracts do not report this exact variant or provide case-specific segregation or de novo evidence.
For PTEN, PP4, PP5, and BP6 are not applicable under the governing VCEP specification.
PS4 and BP5 remain unassigned because the case evidence lacks the required variant-specific phenotype or alternate-diagnosis data.
No exact-variant ClinVar expert-panel classification is present, so PP5 and BP6 cannot be triggered.
The governing PTEN VCEP Version 3.2 framework was applied first. Because this variant is a frameshift, PP3, BP4, and BP7 are all not_applicable; predictor scores must not be used to evaluate these criteria for this consequence type.
Population evidence supports PM2 at Supporting strength only; BA1, BS1, and BS2 are not met because the variant is absent rather than frequent or homozygous in the available gnomAD records.
No criteria match.
Met · 2
PVS1Very strongMet at very strong: the frameshift truncates PTEN at p.Ser338, before the VCEP p.D375 (c.1121) NMD threshold in transcript NM_000314.8.
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Reasoning
NM_000314.8:c.1012_1016del is a frameshift producing NP_000305.3:p.(Ser338LysfsTer3), with the predicted premature termination at codon 340, upstream of the PTEN VCEP decision tree threshold p.D375 (c.1121). The governing PTEN VCEP specification uses NM_000314.8 and assigns PVS1 to nonsense or frameshift variants with a stop codon or disruption at or 5′ to p.D375 when the transcript is biologically relevant and NMD is predicted. PTEN loss of function is an established disease mechanism in this framework, and NM_000314.8 is the preferred biologically relevant transcript. Therefore PVS1 is met at full strength, reported as the literal tier word "very strong".
Rule
PTEN VCEP PVS1 decision tree: frameshift with premature termination at or 5′ to p.D375 (c.1121) in biologically relevant transcript and predicted NMD → PVS1.
Evidence considered
The ClinGen PTEN Expert Panel specification, version 3.2, identifies NM_000314.8 as the preferred transcript and directs use of the PTEN PVS1 decision tree.
The PTEN PVS1 decision tree assigns PVS1 to nonsense or frameshift variants predicted to undergo NMD when the stop codon or disruption is at or 5′ to p.D375 (c.1121) in a biologically relevant transcript.
The normalized consequence is NM_000314.8:c.1012_1016del, a frameshift yielding NP_000305.3:p.(Ser338LysfsTer3), which is upstream of c.1121 and is predicted to introduce a premature termination codon at codon 340.
The PTEN framework establishes loss of function as a disease mechanism, supporting application of PVS1.
Still missing
PVS1_DecisionTree_PTEN.pdf was searched for c.1012_1016del, p.Ser338LysfsTer3, and p.S338Kfs*3; no variant-specific row was present.
The case data do not provide an experimentally measured NMD assay; NMD assignment follows the governing PTEN VCEP positional rule for this upstream frameshift.
PM2SupportingMet, Supporting: the variant is absent from gnomAD v2.1 and v4.1, meeting the PTEN PM2 threshold below 0.00001 (0.001%).
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Reasoning
The ClinGen PTEN Expert Panel Version 3.2 specification permits PM2 at Supporting strength when the variant is absent or present at an allele frequency below 0.00001 (0.001%) in gnomAD or another large sequenced population; if multiple alleles occur in a subpopulation, that subpopulation frequency must be below 0.00002 (0.002%). The variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, satisfying the absence requirement.
Rule
Absent in population; gnomAD or another large sequenced population allele frequency <0.00001 (0.001%), and <0.00002 (0.002%) in any subpopulation with multiple alleles
Evidence considered
The PTEN VCEP Version 3.2 PM2 rule requires absence or allele frequency <0.00001 (0.001%) in gnomAD; any subpopulation with multiple alleles must remain <0.00002 (0.002%).
The default all-comers gnomAD v2.1 record reports the variant absent.
The default all-comers gnomAD v4.1 record reports the variant absent.
PM1Not met: the variant begins at residue 338, outside the PTEN VCEP PM1 catalytic-motif intervals 90–94, 123–130, and 166–168.
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Reasoning
The PTEN VCEP PM1 rule defines the critical functional residues for this criterion as catalytic motifs 90-94, 123-130, and 166-168 on NP_000305.3, with moderate strength. The frameshift begins at residue 338, outside all three VCEP-defined motif intervals. The reviewed PTEN domain summary places residue 338 within the C2 domain (186-351), but that broader domain is not included in the governing VCEP PM1 motif definition, and vcep_materials.json contains no PTEN domain_tables entry expanding the approved list.
Rule
PTEN VCEP PM1 moderate: located in a mutational hotspot and/or critical and well-established functional domain, defined to include residues in catalytic motifs 90-94, 123-130, and 166-168 (NP_000305.3).
Evidence considered
The PTEN VCEP PM1 rule defines critical functional residues as catalytic motifs 90-94, 123-130, and 166-168 on NP_000305.3.
The variant is a frameshift beginning at protein residue 338, which is outside all three VCEP-defined catalytic-motif intervals.
The reviewed PTEN domain summary describes the C2 domain as residues 186-351, including residue 338, but does not establish that this broader domain is an approved PTEN VCEP PM1 interval.
BA1Not met: gnomAD v2.1 and v4.1 report the variant absent, not a filtering allele frequency greater than 0.00056 (0.056%).
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Reasoning
The ClinGen PTEN Expert Panel Version 3.2 specification requires BA1 for a gnomAD filtering allele frequency greater than 0.00056 (0.056%). The variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, so no allele frequency meets or exceeds this stand-alone benign threshold.
Rule
gnomAD filtering allele frequency >0.00056 (0.056%)
Evidence considered
The PTEN VCEP Version 3.2 BA1 rule is filtering allele frequency >0.00056 (0.056%) in gnomAD.
The default all-comers gnomAD v2.1 record reports the variant absent.
The default all-comers gnomAD v4.1 record reports the variant absent.
BS1Not met: gnomAD v2.1 and v4.1 report absence, with no allele frequency in the PTEN BS1 range of 0.0000043 to 0.00056.
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Reasoning
The ClinGen PTEN Expert Panel Version 3.2 specification assigns BS1 Strong for a gnomAD filtering allele frequency from 0.000043 (0.0043%) through 0.00056 (0.056%), and BS1 Supporting from 0.0000043 (0.00043%) through 0.000043 (0.0043%). The variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, providing no frequency in either interval.
Rule
BS1 Strong: gnomAD filtering allele frequency 0.000043 (0.0043%) to 0.00056 (0.056%); BS1 Supporting: 0.0000043 (0.00043%) to 0.000043 (0.0043%)
Evidence considered
The PTEN VCEP Version 3.2 BS1 Strong range is 0.000043 (0.0043%) through 0.00056 (0.056%), and its BS1 Supporting range is 0.0000043 (0.00043%) through 0.000043 (0.0043%).
The default all-comers gnomAD v2.1 record reports the variant absent.
The default all-comers gnomAD v4.1 record reports the variant absent.
BS2Not met: the variant is absent from gnomAD v2.1 and v4.1, with no reported homozygous healthy individual.
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Reasoning
The ClinGen PTEN Expert Panel Version 3.2 specification requires the variant to be observed in the homozygous state in a healthy or PHTS-unaffected individual; one observation is sufficient when homozygosity is confirmed, and two are required when it is unconfirmed. The variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, so no homozygous observation is available.
Rule
Observed in the homozygous state in a healthy or PHTS-unaffected individual; one observation if homozygous status is confirmed, two if not confirmed
Evidence considered
The PTEN VCEP Version 3.2 BS2 rule requires an observed homozygous state in a healthy or PHTS-unaffected individual; confirmed homozygosity requires one observation, otherwise two are required.
The default all-comers gnomAD v2.1 record reports the variant absent.
The default all-comers gnomAD v4.1 record reports the variant absent.
PS2Not assessed: no proband diagnosis, parental testing, maternity/paternity confirmation, or family-history documentation is available for this variant.
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Reasoning
The PTEN VCEP requires a de novo observation with both maternity and paternity confirmed, in a patient with PTEN hamartoma tumor syndrome and no family history, for PS2 at strong strength. The available case evidence contains no proband-level diagnosis, parental testing, maternity or paternity confirmation, or family-history documentation for NM_000314.8:c.1012_1016del, so PS2 cannot be assessed.
Rule
De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.
Evidence considered
The PTEN Expert Panel specification defines PS2 strong as a de novo observation with both maternity and paternity confirmed in a patient with the disease and no family history.
No case-specific proband, parental-testing, or family-history observations were provided in the available case evidence.
Still missing
Document the proband's PTEN hamartoma tumor syndrome diagnosis and phenotype.
Document testing results confirming biological maternity and paternity and the variant's absence in both parents.
Document whether the proband has no relevant family history.
PS4Not assessed: no variant-specific case-control enrichment or phenotype-specificity score is available for comparison with the PTEN PS4 thresholds.
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Reasoning
The PTEN VCEP permits PS4 by either a sufficiently powered case-control study or accumulated phenotype-specificity scores. Its case-control rule requires an odds ratio >2, p<0.05, and a 95% confidence-interval lower limit >1.5; its phenotype route requires independent proband scores of 1-1.5 for Supporting, 2-3.5 for Moderate, 4-15.5 for Strong, or ≥16 for Very Strong. No case-control counts, odds ratio, p-value, confidence interval, Cleveland Clinic scores, pediatric scores, affected proband data, or family-history specificity data are available for this variant. Therefore PS4 cannot be assigned. No numeric comparison is performed because the required variant-specific metric is unavailable.
Rule
PTEN VCEP PS4: case-control odds ratio >2 with p<0.05 and 95% confidence-interval lower limit >1.5; phenotype specificity scores: Supporting 1-1.5, Moderate 2-3.5, Strong 4-15.5, Very Strong ≥16. PS4 may not be applied if BS1 applies and may not be combined with PP4.
Evidence considered
The PTEN VCEP source states that a case-control PS4 route requires odds ratio >2, p<0.05, and a 95% confidence-interval lower limit >1.5.
The PTEN VCEP source assigns phenotype-specificity thresholds of 1-1.5 for Supporting, 2-3.5 for Moderate, 4-15.5 for Strong, and ≥16 for Very Strong.
The available case evidence contains no affected-proband specificity scores, family-history specificity data, or case-control enrichment statistics for NM_000314.8:c.1012_1016del.
Still missing
Variant-specific affected-case and control counts with odds ratio, p-value, and 95% confidence interval.
Independent proband phenotype records sufficient to calculate PTEN Cleveland Clinic or pediatric specificity scores.
PM6Not assessed: no assumed de novo observation, parental results, proband diagnosis, family history, or independent occurrence count is documented.
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Reasoning
The PTEN VCEP allows PM6 for assumed de novo occurrence without confirmed maternity and paternity, with strength determined by the number of independent observations and phenotype specificity. No case-specific de novo observation, parental results, proband diagnosis, family history, or independent occurrences are available for NM_000314.8:c.1012_1016del, so PM6 cannot be assessed.
Rule
Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history.
Evidence considered
The PTEN Expert Panel specification defines PM6 as assumed de novo status without confirmed maternity and paternity, with stronger levels requiring multiple occurrences or a highly specific phenotype.
No case-specific de novo observations or supporting parental and phenotype data were provided in the available case evidence.
Still missing
Document at least one affected proband carrying the variant.
Document parental testing or the basis for assuming de novo status.
Document family history and count independent de novo observations for strength assignment.
If using the phenotype-specific PM6 pathway, document the phenotype-specificity evidence.
PP1Not assessed: no affected relatives, segregation results, phase information, or meiosis count is documented for this variant.
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Reasoning
The PTEN VCEP requires co-segregation with disease in multiple affected family members and assigns supporting, moderate, or strong strength at 3-4, 5-6, or at least 7 meioses, respectively, across the specified family structure. No affected relatives, variant-positive relatives, variant-negative relatives, phase information, or meiosis count is documented for this case, so PP1 cannot be assessed.
Rule
Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.
Evidence considered
The PTEN Expert Panel specification requires 3-4 meioses for PP1 supporting, 5-6 meioses for PP1 moderate, and at least 7 meioses across at least two families for PP1 strong.
No family segregation data or informative meioses were provided in the available case evidence.
Still missing
Identify affected relatives and document their clinical phenotype.
Provide variant testing results for affected and unaffected relatives.
Document informative meioses and phase, including family structure and whether observations are independent.
BS4Not assessed: no affected family members or variant-testing results demonstrate non-segregation in one or more families.
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Reasoning
The PTEN VCEP defines BS4 supporting as lack of segregation in one family and BS4 strong as lack of segregation in affected members of two or more families. No affected family members, relatives tested, variant status, or non-segregation observation is documented for NM_000314.8:c.1012_1016del, so BS4 cannot be assessed.
Rule
Lack of segregation in affected members of one family.
Evidence considered
The PTEN Expert Panel specification defines BS4 supporting as lack of segregation in one family and BS4 strong as lack of segregation in two or more families.
No case-specific non-segregation or family-testing observations were provided in the available case evidence.
Still missing
Document affected relatives and their clinical phenotype.
Document variant-testing results for affected relatives.
Document whether the non-segregating observations come from one family or at least two independent families and assess possible phenocopies.
BP2Not assessed: no second pathogenic PTEN variant or cis/trans phase observation is available to meet the VCEP BP2 rule.
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Reasoning
The PTEN VCEP specifies BP2 at Supporting strength when the variant is observed in trans with a pathogenic or likely pathogenic PTEN variant, or when there are at least three observations in cis and/or with phase unknown involving different pathogenic or likely pathogenic PTEN variants. The available case evidence contains no affected-proband observation, second PTEN variant, phase determination, cis/trans result, or inheritance data for NM_000314.8:c.1012_1016del, so BP2 cannot be assessed.
Rule
Apply BP2 at Supporting strength only if the PTEN VCEP requirement is met: one observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants.
Evidence considered
The ClinGen PTEN Expert Panel specification version 3.2 defines BP2 Supporting as either observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants.
The case evidence provides no qualifying second PTEN variant, affected-proband allelic observation, cis/trans phase result, or inheritance information for NM_000314.8:c.1012_1016del.
Still missing
Documented affected-proband or family observations involving a second pathogenic or likely pathogenic PTEN variant.
Validated cis/trans or phase-unknown status for each qualifying observation.
Inheritance and phase information sufficient to determine whether the variant is in trans or meets the three-observation cis/phase-unknown requirement.
BP5Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN histories are documented.
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Reasoning
The PTEN VCEP allows BP5 at Supporting strength only when the variant is found in at least two cases with an alternate molecular basis, the alternate disorder is highly penetrant, and the patients' personal or family histories show no overlap with PTEN hamartoma tumor syndrome. No such alternate molecular diagnoses, two qualifying cases, penetrance assessment, or non-overlapping personal/family histories are documented for this variant. Therefore BP5 cannot be assigned.
Rule
PTEN VCEP BP5 Supporting: at least two cases with an alternate molecular basis; the other gene/disorder must be highly penetrant; personal and family history must demonstrate no overlap between the other gene/disorder and PTEN.
Evidence considered
The PTEN VCEP requires at least two cases for BP5 and requires a highly penetrant alternate gene/disorder plus no overlap between the alternate disorder and PTEN personal or family history.
The available case evidence does not document two qualifying alternate-molecular-basis cases or the required penetrance and phenotype-history exclusions.
Still missing
At least two variant-positive cases with a documented alternate molecular basis for disease.
Evidence that the alternate disorder is highly penetrant and that each patient's personal or family history does not overlap with PTEN hamartoma tumor syndrome.
Not applicable · 15· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: c.1012_1016del is a frameshift, p.(S338Kfs*3), rather than a missense amino-acid substitution required for this PS1 comparison.
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Reasoning
The PTEN VCEP PS1 rule requires the same amino-acid change as a previously established pathogenic variant, or a different variant at the same nucleotide position as a pathogenic splicing variant. This variant is a frameshift, NP_000305.3:p.(S338Kfs*3), not a missense amino-acid substitution, and no applicable same-amino-acid or pathogenic splicing comparator is documented.
Rule
PTEN VCEP PS1: same amino acid change as a previously established pathogenic variant regardless of nucleotide change, or a different variant at the same nucleotide position as a pathogenic splicing variant with equal or greater predicted impact.
Evidence considered
The PTEN VCEP PS1 rule requires the same amino-acid change as a previously established pathogenic variant or a different variant at the same nucleotide position as a pathogenic splicing variant.
The case variant is NM_000314.8:c.1012_1016del, predicted as NP_000305.3:p.(S338Kfs*3), a frameshift rather than a missense substitution.
PS3N/ANot applicable: the PTEN VCEP functional rule covers high-confidence missense assay entries, whereas this variant is a frameshift absent under all three searched notations.
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Reasoning
The ClinGen PTEN VCEP specification limits the governing Mighell et al. 2018 Table S2 PS3_Moderate rule to high-confidence missense assay entries with Cum_score <= -1.11. NM_000314.8:c.1012_1016del is a frameshift, p.(Ser338LysfsTer3), not a missense variant, and searches of mmc2.xlsx.txt found no exact entry for c.1012_1016del, p.Ser338LysfsTer3, or p.S338Kfs*3. Therefore this missense phosphatase assay rule cannot be applied. The two functional papers in the case bundle also do not mention the exact variant and cannot establish PS3 for it.
Rule
PTEN VCEP PS3: PS3_Moderate may be applied to Mighell et al. 2018 Table S2 high-confidence variants with phosphatase cumulative fitness score <= -1.11; other functional assays may support PS3 only under the specified assay controls and strength rules.
Evidence considered
The PTEN VCEP Version 3.2 specification states PS3_Moderate uses Mighell et al. 2018 Table S2 for high-confidence variants with cumulative phosphatase fitness score <= -1.11.
The PTEN VCEP index declares mmc2.xlsx for PS3 and BS3 and identifies its assay records as missense variants.
Variant normalization identifies NM_000314.8:c.1012_1016del as the frameshift p.(Ser338LysfsTer3) / p.(S338Kfs*3).
The exact variant was not found in mmc2.xlsx.txt under c.1012_1016del, p.Ser338LysfsTer3, or p.S338Kfs*3.
PMID:11237521 and PMID:17218262 were reviewed for functional evidence, but their extracted findings state that the exact variant is not mentioned.
Still missing
No exact entry for c.1012_1016del, p.Ser338LysfsTer3, or p.S338Kfs*3 was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/PTEN/fulltext/mmc2.xlsx.txt; the governing assay table is restricted to missense variants.
PM3VCEPNot applicable: the PTEN VCEP specification explicitly designates PM3 as not applicable for this autosomal-dominant disorder.
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Reasoning
The ClinGen PTEN Expert Panel specification, version 3.2, explicitly designates PM3 as not applicable. PTEN hamartoma tumor syndrome is autosomal dominant in this framework, and no recessive allelic criterion is specified for this gene.
VCEP rule
PM3 is not applicable under the ClinGen PTEN Expert Panel specification version 3.2.
Evidence considered
The ClinGen PTEN Expert Panel specification version 3.2 lists PM3 as Not Applicable.
The same specification identifies PTEN hamartoma tumor syndrome as autosomal dominant.
PM4N/ANot applicable: the variant is a frameshift with a premature stop, whereas PTEN PM4 covers in-frame length changes or stop-loss extensions.
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Reasoning
PM4 is not applicable under the governing PTEN VCEP specification because its rule is restricted to protein-length changes caused by in-frame insertions or deletions in a non-repeat region, including catalytic-motif in-frame changes, and to stop-loss protein extensions. This variant is a frameshift with a premature termination codon, not an in-frame indel or stop-loss variant.
Rule
PTEN VCEP PM4 applicability: in-frame insertion/deletion in a non-repeat region or stop-loss protein extension only.
Evidence considered
The ClinGen PTEN Expert Panel specification, version 3.2, limits PM4 to in-frame insertions or deletions affecting a non-repeat region and to stop-loss variants causing protein extension.
NM_000314.8:c.1012_1016del is a frameshift producing p.(Ser338LysfsTer3), so it does not satisfy the PTEN PM4 applicability rule.
PM5N/ANot applicable: PM5 requires a missense change at a residue with a pathogenic or likely pathogenic alternate missense change, whereas this variant is a frameshift.
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Reasoning
The PTEN VCEP PM5 rule requires a missense change at an amino-acid residue where a different pathogenic or likely pathogenic missense change has been observed, with the interrogated variant's BLOSUM62 score no greater than the known variant. This variant is a frameshift, not a missense change, so the rule does not apply.
Rule
PTEN VCEP PM5 moderate: missense change at a residue where a different pathogenic or likely pathogenic missense change has been seen, with the interrogated variant's BLOSUM62 score equal to or less than the known variant.
Evidence considered
The PTEN VCEP PM5 rule requires a missense change at an amino-acid residue with a previously observed pathogenic or likely pathogenic different missense change and a BLOSUM62 comparison.
The case variant is NM_000314.8:c.1012_1016del, predicted as p.(S338Kfs*3), a frameshift and therefore ineligible for the VCEP's classic same-residue missense PM5 rule.
PP2N/ANot applicable: the PTEN VCEP PP2 rule is missense-specific, while this variant is the frameshift p.(S338Kfs*3).
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Reasoning
The PTEN VCEP PP2 rule applies to a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. This variant is a frameshift, so the missense-specific PP2 rule is not applicable.
Rule
PTEN VCEP PP2 supporting: missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Evidence considered
The PTEN VCEP PP2 rule requires a missense variant in a gene with a low rate of benign missense variation and a common missense disease mechanism.
The case variant is a frameshift, NP_000305.3:p.(S338Kfs*3), not a missense variant.
PP3N/ANot applicable: the variant is a frameshift, p.(S338Kfs*3), outside PP3's calibrated missense and splice-impact scope.
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Reasoning
Not applicable: the variant is a frameshift, NP_000305.3:p.(S338Kfs*3), which is a protein-length-changing truncating consequence outside the calibrated scope of PP3. The PTEN VCEP specification limits PP3 computational support to splicing variants assessed with concordant SpliceAI and VarSeak or missense variants assessed with REVEL; no predictor was evaluated for this out-of-scope frameshift.
Evidence considered
The case variant is NM_000314.8:c.1012_1016del with consequence class frameshift and protein change NP_000305.3:p.(S338Kfs*3).
The PTEN VCEP Version 3.2 specification defines PP3 computational support for splicing variants using concordant SpliceAI and VarSeak or for missense variants using REVEL; it does not extend PP3 to frameshift variants.
PP4VCEPNot applicable: the PTEN VCEP incorporates phenotype specificity into PS4 and marks PP4 as not applicable.
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Reasoning
The PTEN VCEP marks PP4 as not applicable and explicitly incorporates phenotype specificity into PS4 Use 2. PP4 is therefore not assessed separately for this PTEN variant.
VCEP rule
PTEN VCEP PP4: Not applicable; phenotype specificity is incorporated into PS4 Use 2.
Evidence considered
The PTEN VCEP lists PP4 as not applicable and states that phenotype specificity is incorporated into PS4 Use 2.
PP5VCEPNot applicable: the PTEN VCEP excludes PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification.
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Reasoning
The PTEN VCEP marks PP5 as not applicable. Independently, the exact variant is reported as absent from ClinVar, so there is no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification that could support PP5. OncoKB's variant-specific Likely Oncogenic label is not a ClinVar expert-panel assertion and does not trigger PP5.
VCEP rule
PP5 requires an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification, but the PTEN VCEP marks PP5 not applicable.
Evidence considered
The PTEN VCEP states that PP5 is not applicable for this VCEP.
The ClinVar search found no record for NM_000314.8:c.1012_1016del.
No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion is available; ordinary or non-ClinVar classifications would not qualify under the requested rule.
BS3N/ANot applicable: the PTEN VCEP benign functional rules require applicable missense or splicing assay evidence, but this frameshift has no exact entry under the searched variant notations.
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Reasoning
The ClinGen PTEN VCEP specification limits the governing Mighell et al. 2018 Table S2 BS3_Supporting rule to high-confidence missense assay entries with Cum_score > 0; other BS3 protein-function evidence is likewise specified for missense variants or for intronic/synonymous splicing assays. NM_000314.8:c.1012_1016del is a frameshift, p.(Ser338LysfsTer3), not a missense, and searches of mmc2.xlsx.txt found no exact entry for c.1012_1016del, p.Ser338LysfsTer3, or p.S338Kfs*3. Therefore BS3 cannot be applied. The two functional papers in the case bundle also do not mention the exact variant and cannot establish BS3 for it.
Rule
PTEN VCEP BS3: BS3_Supporting may be applied to Mighell et al. 2018 Table S2 high-confidence variants with phosphatase cumulative fitness score > 0; BS3 also requires specified no-impact splicing or validated protein-function assays as applicable.
Evidence considered
The PTEN VCEP Version 3.2 specification states BS3_Supporting uses Mighell et al. 2018 Table S2 for high-confidence variants with cumulative phosphatase fitness score > 0.
The PTEN VCEP specification describes additional BS3 protein-function evidence for missense variants and no-impact splicing evidence for intronic or synonymous variants.
Variant normalization identifies NM_000314.8:c.1012_1016del as the frameshift p.(Ser338LysfsTer3) / p.(S338Kfs*3).
The exact variant was not found in mmc2.xlsx.txt under c.1012_1016del, p.Ser338LysfsTer3, or p.S338Kfs*3.
PMID:11237521 and PMID:17218262 were reviewed for functional evidence, but their extracted findings state that the exact variant is not mentioned.
Still missing
No exact entry for c.1012_1016del, p.Ser338LysfsTer3, or p.S338Kfs*3 was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/PTEN/fulltext/mmc2.xlsx.txt; the governing assay table is restricted to missense variants.
BP1VCEPNot applicable: the PTEN VCEP explicitly marks BP1 as not applicable, and this case variant is a truncating frameshift rather than a missense variant.
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Reasoning
The PTEN VCEP marks BP1 as not applicable. In addition, the generic BP1 concept is intended for missense variants in a gene where truncating variants cause disease but missense variants are not a common mechanism; this case variant is itself a truncating frameshift.
VCEP rule
PTEN VCEP BP1 applicability: Not Applicable.
Evidence considered
The PTEN VCEP specification marks BP1 as Not Applicable.
The case variant is the truncating frameshift NP_000305.3:p.(S338Kfs*3), not a missense variant.
BP3VCEPNot applicable: the PTEN VCEP marks BP3 as not applicable, and this variant is a truncating frameshift rather than a repeat-region in-frame deletion.
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Reasoning
BP3 is not applicable under the governing PTEN VCEP specification, which explicitly marks BP3 as Not Applicable. In addition, this variant is a protein-truncating frameshift rather than an in-frame deletion in a repetitive region.
VCEP rule
PTEN VCEP BP3 applicability: Not Applicable.
Evidence considered
The ClinGen PTEN Expert Panel specification, version 3.2, explicitly lists BP3 as Not Applicable.
The variant consequence is a frameshift with a premature termination codon, not an in-frame deletion in a repetitive region.
BP4N/ANot applicable: the variant is a frameshift, p.(S338Kfs*3), outside BP4's calibrated missense and splice-impact scope.
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Reasoning
Not applicable: the variant is a frameshift, NP_000305.3:p.(S338Kfs*3), which is a protein-length-changing truncating consequence outside the calibrated scope of BP4. The PTEN VCEP specification limits BP4 computational support to splicing variants assessed with concordant SpliceAI and VarSeak or missense variants assessed with REVEL; no predictor was evaluated for this out-of-scope frameshift.
Evidence considered
The case variant is NM_000314.8:c.1012_1016del with consequence class frameshift and protein change NP_000305.3:p.(S338Kfs*3).
The PTEN VCEP Version 3.2 specification defines BP4 computational support for splicing variants using concordant SpliceAI and VarSeak or for missense variants using REVEL; it does not extend BP4 to frameshift variants.
BP6VCEPNot applicable: the PTEN VCEP excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.
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Reasoning
The PTEN VCEP marks BP6 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The exact variant is also absent from ClinVar, so no exact-variant ClinVar expert-panel Benign or Likely benign classification exists to support BP6 under the requested rule.
VCEP rule
BP6 requires an exact-variant ClinVar expert-panel Benign or Likely benign classification, but the PTEN VCEP marks BP6 not applicable.
Evidence considered
The PTEN VCEP states that BP6 is not applicable and is not for use under the ClinGen SVI VCEP Review Committee recommendation.
The ClinVar search found no record for NM_000314.8:c.1012_1016del.
No exact-variant ClinVar expert-panel Benign or Likely benign assertion is available; ordinary or non-expert assertions would not qualify under the requested rule.
BP7N/ANot applicable: the variant is a frameshift, p.(S338Kfs*3), not the synonymous variant required for BP7.
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Reasoning
Not applicable: the variant is a frameshift, NP_000305.3:p.(S338Kfs*3), not a synonymous variant. BP7 is therefore out of scope before splice-prediction evidence is considered, and no SpliceAI or other computational score was evaluated for BP7.
Evidence considered
The case variant is NM_000314.8:c.1012_1016del with consequence class frameshift and protein change NP_000305.3:p.(S338Kfs*3).
The PTEN VCEP Version 3.2 specification defines BP7 for synonymous or qualifying intronic variants with no predicted splice impact; a frameshift variant is outside that scope.
Every interpreted variant in PTEN, mapped onto the exon structure of NM_000314.8. Select a row to find it on the plot.
PTENNM_000314.8
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PTEN—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -166 bp
0.015
SpliceAI acceptor gainat +83 bp
0.000
SpliceAI donor lossat +15 bp
0.002
SpliceAI donor gainat -189 bp
0.011
Pangolin splice lossmagnitude shown
-0.064
Pangolin splice gain
0.013
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: the variant is a frameshift, p.(S338Kfs*3), outside PP3's calibrated missense and splice-impact scope.
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Reasoning
Not applicable: the variant is a frameshift, NP_000305.3:p.(S338Kfs*3), which is a protein-length-changing truncating consequence outside the calibrated scope of PP3. The PTEN VCEP specification limits PP3 computational support to splicing variants assessed with concordant SpliceAI and VarSeak or missense variants assessed with REVEL; no predictor was evaluated for this out-of-scope frameshift.
Evidence considered
The case variant is NM_000314.8:c.1012_1016del with consequence class frameshift and protein change NP_000305.3:p.(S338Kfs*3).
The PTEN VCEP Version 3.2 specification defines PP3 computational support for splicing variants using concordant SpliceAI and VarSeak or for missense variants using REVEL; it does not extend PP3 to frameshift variants.
BP4N/ANot applicable: the variant is a frameshift, p.(S338Kfs*3), outside BP4's calibrated missense and splice-impact scope.
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Reasoning
Not applicable: the variant is a frameshift, NP_000305.3:p.(S338Kfs*3), which is a protein-length-changing truncating consequence outside the calibrated scope of BP4. The PTEN VCEP specification limits BP4 computational support to splicing variants assessed with concordant SpliceAI and VarSeak or missense variants assessed with REVEL; no predictor was evaluated for this out-of-scope frameshift.
Evidence considered
The case variant is NM_000314.8:c.1012_1016del with consequence class frameshift and protein change NP_000305.3:p.(S338Kfs*3).
The PTEN VCEP Version 3.2 specification defines BP4 computational support for splicing variants using concordant SpliceAI and VarSeak or for missense variants using REVEL; it does not extend BP4 to frameshift variants.
BP7N/ANot applicable: the variant is a frameshift, p.(S338Kfs*3), not the synonymous variant required for BP7.
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Reasoning
Not applicable: the variant is a frameshift, NP_000305.3:p.(S338Kfs*3), not a synonymous variant. BP7 is therefore out of scope before splice-prediction evidence is considered, and no SpliceAI or other computational score was evaluated for BP7.
Evidence considered
The case variant is NM_000314.8:c.1012_1016del with consequence class frameshift and protein change NP_000305.3:p.(S338Kfs*3).
The PTEN VCEP Version 3.2 specification defines BP7 for synonymous or qualifying intronic variants with no predicted splice impact; a frameshift variant is outside that scope.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
PTEN: life as a tumor suppressor.
This review describes PTEN as a 403-amino-acid protein with a phosphatase domain at residues 1-185 and a C2 domain at residues 186-351, which encompasses residue 338. It does not report or experimentally evaluate c.1012_1016del or p.(S338Kfs*3).
PTEN is a 403-amino-acid protein which contains a phosphatase domain (residues 1–185) in the N-terminal region with the phosphatase motif (HCXXGXXR; residues 123–130) essential for its tumor-suppressor activity. PTEN contains a C2 domain (residues 186–351), which allows for the binding of PTEN to phospholipids, perhaps for the effective positioning of PTEN at the membrane.
Figure 2 caption; DOMAIN STRUCTURE OF PTEN section
Essential role for nuclear PTEN in maintaining chromosomal integrity.
The paper does not mention PTEN c.1012_1016del or NP_000305.3:p.(S338Kfs*3). It reports functional effects of other C-terminally truncated PTEN mutants in cell-based assays, but the specific variant in question was not experimentally evaluated.
Our data demonstrate that the C-terminal domain of PTEN is required for its association with centromeres and CENP-C since the truncated mutant PTEN189 no longer interacts.
Results, “Physical Association of PTEN with Centromeres Is Crucial for Chromosome Stability,” paragraph describing PTEN189; Cell 128, p. 161
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
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